CANDIDATE: Amy L. Sindler, Ph.D., is a cardiovascular physiologist in Integrative Physiology at the University of Colorado Boulder. In this amended application, Dr. Sindler's research aims to provide new insight into a novel pathway (impaired nicotinamide adenine dinucleotide [NAD+] bioavailability) by which aging and chronic kidney disease (CKD), independently and when occurring together, produce vascular and renal dysfunction associated with increased risk of cardiovascular diseases (CVD). She will also determine the efficacy of a novel NAD+ boosting compound as a potential therapeutic strategy. Her immediate goal is to acquire the research training and professional skills necessary to transition to an independent investigator. Her long-term goal is to develop a successful, independent, extramurally funded research program identifying novel pathways and the effectiveness of interventions to treat vascular and renal dysfunction to reduce CVD risk in CKD. CAREER DEVELOPMENT PLAN: Dr. Sindler's research career development training consists of: 1) acquiring new experimental skills and approaches to strengthen her research plan; 2) further training in geriatrics and biostatistics; and 3) refinement of professional skills development including formal course work, attendance and presentations at weekly journal clubs, university seminars, national scientific meetings, as well as Renal and Geriatric Grand Round Series and through regular interactions with her mentoring team. ENVIRONMENT: The environment for Dr. Sindler's training plan will be outstanding. The principal mentor, Dr. Seals, and co-mentor Dr. Levi, are internationally recognized and NIA funded scientists with strong records of successful mentoring in biomedical research pertaining to vascular dysfunction, aging, CKD and CVD risk. Consulting-mentor Dr. Schwartz is PI on a long-standing NIA T32, thus perfect for developing general career skills in aging-geriatrics, Dr. Imai is the leading expet in NAD+ biology and aging, and Dr. McQueen is director of biostatistics in several research centers on campus. Dr. Sindler's mentorship team will provide specific expertise in key areas of her research project and overall training plan. RESEARCH: CVD are the leading cause of death in older patients with CKD. CVD risk is attributable in large part to vascular dysfunction, primarily stiffening of the large elastic arteries and endothelial dysfunction. However, the mechanisms by which aging and CKD interact to produce vascular and renal dysfunction and increase CVD risk is unknown. The proposed research seeks to provide insight into a novel pathway, impaired NAD+ bioavailability, by which aging and CKD interact to increase CVD risk, as well as the efficacy of an NAD+ boosting therapy. Aim 1 will assess vascular and renal function with aging and CKD in 2 different mouse strains with differing susceptibility to renal damage/dysfunction. Aim 2 will determine the role of impaired NAD+ on vascular and renal dysfunction with aging and CKD, as well as the efficacy of an NAD+ boosting therapy to treat vascular and renal dysfunction. Results from this study will provide the evidence needed to translate these findings to older patients with CKD.